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Objective Friedreich ataxia ( FRDA) is an autosomal recessive ataxia resulting from mutations in the frataxin gene ( FXN). Such mutations, usually expanded guanine-adenine-adenine ( GAA) repeats, give rise to decreased levels of frataxin protein in both affected and unaffected tissues. The goal was to understand the relationship of frataxin levels in peripheral tissues to disease status. Methods Frataxin levels were measured in buccal cells and blood, and analyzed in relation to disease features. Site-directed mutant frataxin was also transfected into human embryonic kidney cells to model results from specific point mutations. Results There was no evidence for change in frataxin levels over time with repeated measures analysis, although linear regression analysis of cross-sectional data predicted a small increase over decades. GAA repeat length predicted frataxin levels in both tissues, and frataxin levels themselves predicted neurological ratings (accounting for age). Compound heterozygous patients for a GAA expansion and a point mutation in FXN generally had lower levels of frataxin than those homozygous for the presence of two GAA repeat expansions, though levels varied dramatically between tissues in some compound heterozygotes for point mutations. The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo. Start codon mutations led to low levels of frataxin in buccal cells but preserved immunoreactive frataxin levels in blood. Interpretation The present data show that peripheral frataxin levels reflect disease features in FRDA, but emphasize the need for interpretation of such levels in the context of specific mutations. [ABSTRACT FROM AUTHOR]

Friedreich ataxia is the most common inherited ataxia, with a wide phenotypic spectrum. It is generally caused by GAA expansions on both alleles of FXN, but a small percentage of patients are compound heterozygotes for a pathogenic expansion and a point mutation. Two recent diagnostic innovations are further characterizing individuals with the phenotype but without the classic genotypes. First, lateral-flow immunoassay is able to quantify the frataxin protein, thereby further characterizing these atypical individuals as likely affected or not affected, and providing some correlation to phenotype. It also holds promise as a biomarker for clinical trials in which the investigative agent increases frataxin. Second, gene dosage analysis and the identification of affected individuals with gene deletions introduce a novel genetic mechanism of disease. Both tests are now clinically available and suggest a new diagnostic paradigm for the disorder. Genetic counseling issues and future diagnostic testing approaches are considered as well. [ABSTRACT FROM AUTHOR]

Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia, dysarthria, and areflexia. The authors report the progress of a large international noninterventional cohort (n = 410), tracking the natural history of disease progression using the neurologic examination-based Friedreich Ataxia Rating Scale. The authors analyzed the rate of progression with cross-sectional analysis and longitudinal analysis over a 2-year period. The Friedreich Ataxia Rating Scale captured disease progression when used at 1 and 2 years following initial evaluation, with a lower ratio of standard deviation of change to mean change over 2 years of evaluation. However, modeling of disease progression identified substantial ceiling effects in the Friedreich Ataxia Rating Scale, suggesting this measure is most useful in subjects before maximal deficit is approached. [ABSTRACT FROM AUTHOR]

Objective: Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease. Recent medical advances have improved the average life expectancy, and as such, many female patients are contemplating pregnancy. However, little research exists exploring the medical or psychosocial complications that arise from pregnancy with this disease. Study Design: In this study, we retrospectively examined 31 women with FRDA who had 65 pregnancies, resulting in 56 live offspring. Results: FRDA did not appear to increase the risk of spontaneous abortion, preeclampsia, or preterm birth. Despite the sensory and proprioceptive loss that occurs in FRDA, nearly four fifths of births were vaginal. Of babies, 94.4% were discharged home with their mothers. Equal numbers of women reported that pregnancy made their disease symptoms worse, better, or unchanged. Conclusion: This study demonstrates that women with FRDA can have uncomplicated pregnancies that do not uniformly complicate disease symptomatology. [ABSTRACT FROM AUTHOR]